4/9/13
1
Parkinson’s Disease Foundation
PD ExpertBriefing: Medical Therapies: What's in the Parkinson's Pipeline?
Led By: Kapil D. Sethi, M.D., F.R.C.P.
Georgia Regents University, Augusta, GA
To hear the session live on: Tuesday, April 16, 2013
at 1:00 PM ET.
DIAL: 1 (888) 272-8710 and enter the passcode 6323567#.
To also view the session live on the computer by visiting:
http://event.netbriefings.com/event/pdeb/Live/therapies/
If you have any questions, please contact: Valerie Holt at [email protected] or call (212) 923-4700
1
2
Introduction & Welcome by Robin Elliott
Executive Director Parkinson’s Disease Foundation
4/9/13
2
Medical Therapies: What's in the Parkinson's Pipeline?
Kapil D. Sethi, M.D., F.R.C.P., F.A.A.N. Professor of Neurology
Director, Movement Disorders Program Medical College of Georgia at Georgia Regents University
Augusta, Georgia Senior Medical Expert, Merz Pharmaceuticals
3
Why Do We Need New Medications for Parkinson’s Disease?
• There is no drug/intervention that has been demonstrated conclusively to slow down the rate of clinical decline in Parkinson’s disease.
• The existing drugs that benefit motor symptoms have limitations: – levodopa results in motor complication – dopamine agonists have neuropsychiatric
side effects
4
4/9/13
3
Why Do We Need New Medications for Parkinson’s Disease?
• The burden of nonmotor symptoms such as autonomic disturbances, cognitive problems and gait and balance issues in not adequately addressed by the currently available medications.
5
These Will Not Be There! • Vitamin E (antioxidant) • Coenzyme Q10
• Minocycline (anti-inflammatory) • CEP-1347 (JUNK inhibitor) • Talampanel (AMPA receptor antagonist) • GPI-1485 (immunophilin ligand) • Istradefylline (A2A antagonist) • Riluzole (glutamate release inhibitor) • Sarizotan (5HT1A receptor agonist and weak D2 antagonist) • Tesofensine (triple uptake inhibitor) • TCH-346 (anti-apototic) • Pardoprunox (a partial agonist at dopamine D2 and D3 receptors) • Perampanel (AMPA receptor antagonist)
6
4/9/13
4
Medications in Development
• There are currently over 100 new therapies under development for Parkinson’s disease (PD).1 These include drugs aimed at – Disease modification/neuroprotection – Symptomatic management
• Motor symptoms • Nonmotor symptoms
1. Thomson-Reuters Pharmaceuticals. 2012. 7
8
Neuroprotection vs Slowing the Clinical Progression
• Neuroprotection, or disease modification, in PD can be defined as an intervention that protects or rescues vulnerable neurons and thereby slows, stops, or reverses disease progression
• Slowing the clinical progression refers to reducing the rate of worsening of clinical signs and symptoms without alluding to the underlying mechanism
4/9/13
5
Barriers to Developing Neuroprotective Therapies in PD
• Lack of a clear understanding about the biological processes leading to cell death in PD
• Lack of a faithful animal model
• Inadequate translational research
• Heterogeneity in people with PD
• Lack of means to determine the proper dose to study neuroprotection
• Lack of a biomarker leading to reliance on clinical measures that may be influenced by the therapy itself
9
10
Some Currently Ongoing Neuroprotective Therapy Trials
• National Institutes of Heath (NIH) neuroprotective studies – Creatine (ongoing Phase II/III study-NET PD) – FS-ZONE (pioglitazone)
• Pilot studies – Isradipine (dihydropyridine Ca2+ channel
blocker) – Inosine (antioxidant, elevates urate levels)
4/9/13
6
Pioglitazone • FS-ZONE Phase 2 NET-PD
• Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-G) also known as glitazone receptor and to a lesser extent PPAR-alpha
• This leads to anti-inflammatory and anti-apoptotic effects
11
Another Approach to Neuroprotection
Chan CS, et al. Nature. 2007;447(7148):1081-1086.
Systemic delivery of isradipine was neuroprotective in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine 6-(OHDA) models of PD in mice.
Isradipine pellets
• Substantia nigra pars compacta (SNc) neurons are autonomous pacemakers
• Pacemaking properties are unique for SNc and not present in ventral tegmental area (VTA) neurons
• Pacemaker affinity changes from Na+ to Ca2+ with aging
• Ca2+ dependence can be reversed back to Na+ with CaV1.3 Ca2+ channel blockers
12
4/9/13
7
Other Drugs
• High serum urate levels predict slower decline of function in people with PD.
• Inosine is being studied in 90 people with early PD to assess its safety and its ability to raise CSF urate levels.
13
Growth Factors • GDNF and BDNF are important for neuronal
survival and recovery from injury
• While the open-label studies of direct infusion of GDNF into striatum were positive, the double-blind (AMGEN) study was negative
• AAV-Neurturin employs a vector to transfer the gene that makes Neurturin directly into brain cells most affected by PD
• One double-blind study negative, but nigral and putamen targeting with higher dose under study
14
4/9/13
8
Oral Agent PYM 50028-Cogane
15
Oral Agent to Enhance NGF
• Cogane (PYM50028) is an oral non-peptide compound that crosses BBB and induces nerve growth factors (NGF) in dopaminergic and nondopaminergic neurons
• Results in over 40% improvement in parkinsonism in the MPTP primate model
• Unfortunately the Phase II trial failed to meet the endpoints
16
4/9/13
9
Future Targets
• Agents to inhibit hyperphosphorylation of alpha- synuclein
• Agents to inhibit alpha synuclein transfer from one cell to the other
• Novel kinase inhibitors for targeted populations such as LRRK2 related PD
17
Cocktail Therapy – Future of PD
• Multiple pathways involved leading to cell death
• All people with PD are not the same
• In other fields like cancer, and tuberculosis success achieved with strategic combinations of drugs acting on different pathways
18
4/9/13
10
19
Management of PD Motor Disability
A Little History Reserpine Monkey Model
20
4/9/13
11
Levodopa remains the most potent medication for
symptomatic control of Parkinson’s
21
Improving delivery of current drugs or creating novel formulations of existing
medications
22
4/9/13
12
Levodopa Therapy – Future • Long-acting levodopa –Rytary- IPX066
(IMPAX) – Clinical trials in de novo and advanced PD – Two Phase III studies, APEX-PD and more
recent ADVANCE-PD, study show superiority over conventional levodopa
• Another drug XP21279 is a slow release formulation of levodopa that is absorbed throughout the small intestine and the early results are encouraging
–
23 1. Blindauer K, et al. Arch Neurol. 2006;63(2):210-216.
Levodopa Therapy-The Future
• Levodopa Patch preparation abandoned by Neuroderm Israel due to skin irritation
• In the future Highly concentrated subcutaneous pumps and programmable patches may be developed
• Intrajejunal infusion of levodopa (DUODOPA)
24
4/9/13
13
Novel Formulations of Existing Medications
1. Carbidopa patch (ND0611) under development. Seems to reduce peripheral side effects of levodopa and improve pharmacokinetics hopefully resulting in more “on” time.
2. Long acting amantadine for dyskinesia being developed by ADAMAS pharmaceuticals.
3. Some ongoing discussions about developing a COMT patch.
4. A COMT inhibitor that is as potent as tolcapone (Tasmar) but without liver concerns.
25
Optimization of Dopamine Agonist Delivery
• Long-acting dopamine agonist – Ropinirole XL – Pramipexole ER – Rotigotine patch – is back again! – Lisuride patch in development
• Dopamine agonist continuous delivery – Apomorphine pump Subcutaneous1 – Lisuride pump Subcutaneous2
26
1. Stocchi F. Neurol Sci. 2008;29(Suppl 5):S383-S386.
2. Heinz A, et al. J Neural Transm Gen Sect. 1992;90(2):145-150.
4/9/13
14
Management of PD Motor Complications- New Formulations of Existing Therapies
Continuous drug administration a competition to deep brain stimulation (DBS) surgery? • DUODOPA
– Intrajejunal levodopa gel delivery1,2 – Double-blind and open-label US studies
show clear benefit • Subcutaneous apomorphine infusion
– Not yet studied in the United States – The problems of skin irritation and nodules
has to be tackled and it will enhance utility
27
1. Nyholm D, et al. Clin Neuropharmacol. 2008; 31(2):63-73. 2. Devos, D; French DUODOPA Study Group. Mov Disord. 2009;24(7):993-1000. 3. Goetz CG, et al. Mov Disord. 2007;22(2):179-186.
MAO-B Inhibitors - Safinamide
• A selective, reversible MAO-B inhibitor 1000 times more selective for B than A with no tyramine effect.
• Voltage-dependent sodium and N-type calcium channel blocker, and inhibits glutamate release.
• May protect against seizures and may improve cognition.
• Development process has been long and frustrating!
28 Ebersbach G, Stöck M, Müller J, Wenning G, Wissel J, Poewe W. Mov Disord. 1999 Nov;14(6):1011-3.Worsening of motor performance in patients with Parkinson's disease following transdermal nicotine administration.
4/9/13
15
Medications with Novel Mechanisms
• A2A antagonists (GABAA inhibition of globus pallidus)-caffiene is one of them! – Istradefylline-is coming back
• Positive results in Phase 3 trials1 • Food and Drug Administration (FDA) did
not grant approval in March 2008 – Other A2A antagonists in development:
preladenent, SYN115
29
1. Lewitt PA, et al. Ann Neurol. 2008;63(3):295-302.
Medications with Novel Mechanisms
• Serotonin receptor partial agonists – Target dyskinesia – Sarizotan 5HT1A agonist
failed – Alpha adrenergic antagonists – fipamazole
• Nicotine receptor agonists – Strong epidemiological data re smoking2 – Clinical trials so far negative3,4
30
1. Lewitt PA, et al. Ann Neurol. 2008;63(3):295-302. 2. Quik M, et al. Mov Disord. 2008;23(12):1641-1652. 3. Ebersbach G, 2001. 4. Lemay S, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(1):31-39.
4/9/13
16
Adenosine A2A Receptors • Changes in relative activities of direct (underactive)
and indirect (overactive) pathways in PD
• Levodopa corrects changes in the direct pathway (D1 excitation) but not indirect (continued elevation of enkephalin mRNA), which relates to D2 inhibition – resulting in dyskinesias
• Mismatch of direct and indirect pathways
• Stimulation of A2A reduces D2 receptor affinity
• Antagonist will increase dopamine affinity to D2 receptors, hence inhibiting the indirect pathway
• Co-administration of A2A antagonist and apomorphine prevents dyskinesia
31
Preladenant – SCH 420814 • Phase I and II studies most recently doses used were 1,
2, 5, and 10 mg twice daily
• Doses well tolerated with LD; improved motor function (UPDRS) and improved “on” time
• Most frequent side effects dizziness and headache
• BP increases noted but diminished with continued therapy
• Asymptomatic liver enzyme (ALT) elevation on or after week 4; 25% with high doses (>25 mg/day) and a third 3x the ULN (cholestasis) NOT in the 10 mg twice daily group
32
4/9/13
17
• AFQ056 (Novartis) a metabotropic glutamate receptor 5 (mGluR5) antagonist, has recently showed positive results in a proof-of-concept trial in PD-LID
• Psychosis still an issue with mGLuR5 antagonists
Treating Levodopa Induced Dyskinesia Glutamate Receptor Antagonists
33
Dipragluran
• MGluR 5 antagonist forund to have positive results in a Phase II study in people with with Levodopa-induced dyskinesias
• Named as one of the Top 10 “Neurocience Projects to Watch” by I don’t know who!
• Phase III studies are planned
34
4/9/13
18
Fipamezole (FJORD) Study
• Primary study – No significant change in levodopa-induced dyskinesias
(LIDs) rating for the combined US and Indian study groups
• Secondary analysis – US subset (65% of the total study population) – Strong evidence of FIP efficacy against LID – Highest dose of FIP tested (90 mg, three times daily) may be
useful to treat LID in advanced PD • Without making the PD worse
• Indian study subset – Lack of antidyskinetic efficacy unexplained!! I have an idea!
35
Lewitt PA, Hauser RA, Lu M, Nicholas AP, Weiner W, Coppard N, Leinonen M, Savola JM Randomized clinical trial of fipamezole for dyskinesia in Parkinson disease (FJORD study).. Neurology. 2012 Jul 10;79(2):163-9. Epub 2012 Jun 27.
Treating Nonmotor Problems
• PD Psychosis including hallucination affects a large number of patients.
• Currently atypical antipsychotics such as Seroquel and Clozaril are used to treat PDP but these have limitations.
• Pimvanserin-A 5 HT2A antagonist and inverse agonist is being studied in Phase III studies
• So far results are encouraging.
36
4/9/13
19
Agonists, Antagonists and Inverse Agonists
37
Treating Nonmotor Manifestations
38
Lubiprostone studied in PD constipation – small DB study positive Ondo 2012
4/9/13
20
Constipation Secondary to Puborectalis Syndrome
Treatment: use an Indian toilet.! 39
Treating Orthostatic Hypotension
• Droxidopa (3-4 l-threo-DOPS) is norepinephrine precursor
Droxidopa Norephinephrine
• Clinically it appears that carbidopa will not impair its action and the drug will be useful for hypotension due to multiple etiologies
40
DDCI
4/9/13
21
Pharmacogenetics
• It has been known since the 1950s that a certain number of people lack butylcholinesterase and can have a severe reaction with succinylcholine.
• In the 1950s, a number of African American soldiers receiving antimalarial drugs developed hemolysis due to G6 PD deficiency.
• In the field of PD, this field is in its infancy.
41
Should Sergey Brin be on CEP-1347??
42
4/9/13
22
Increase in “ON” time and the AOC Increased More after ENT in COMTHH than in COMTLL Patients
.
43
Corvol JC, Bonnet C. et al. The COMT Val158Met polymorphism affects the response to entacapone in Parkinson's disease: a randomized crossover clinical trial. Ann Neurol. 2011 Jan;69(1):111-8. doi: 10.1002/ana.22155.
Hope Yogi Berra was wrong when he said, “The Future Ain't What It Used To Be.”
44
4/9/13
23
Questions & Answers
45
Resources from PDF
Fact Sheets • Understanding
PD Medications • Medication Log
Parkinson’s Disease Resource List • 750 Resources
Online • PD ExpertBriefing: Complementary Approaches to PD • Online Course: Parkinson's Advocates in Research
46
4/9/13
24
Upcoming PD ExpertBriefings
Improving Communication in Parkinson’s: One Voice, Many Listeners Tuesday, June 4, 1:00 PM – 2:00 PM ET Angela Roberts-South, M.A., C.C.C.-S.L.P., C.A.S.L.P.O .(Reg.), Ph.D. Candidate, Western University, Ontario, Canada Sex and Parkinson's Tuesday, September 10, 1:00 PM - 2:00 PM ET Gila Bronner, M.P.H., M.S.W., C.S.T. Sexual Medicine Center, Sheba Medical Center, Israel
47
Please complete our SURVEY.
Your responses help us to improve
the work that we do.
Thank you.
48